The focus at the National Cancer Institute continues to be on increasing survivorship and on enhancing the quality of life for cancer survivors. One contribution toward this goal would be to identify environmental factors that contribute to cancer survivorship, including nutritional factors that are commonly recommended for supplementation in cancer complementary and alternative medicine (CAM). The optimal vitamin nutriture of cancer patients is not well established. Our preliminary data provide evidence that rapid depletion of the vitamin folic acid is associated with increased resistance of cultured human lung cancer cells to the chemotherapeutic agent cisplatin. The overall goal of this project is to examine the hypothesis that folic acid influence the resistance in cancer cells to the action of agents used for cancer chemotherapy. We hypothesize, based on our preliminary data, that folic acid will prevent intrinsic and acquired resistance to anticancer agents commonly used in lung and ovarian cancer chemotherapy. To test this hypothesis, we propose the following three Specific Aims: Specific Aim 1: To determine whether high doses of folic acid can inhibit development of resistance to cisplatin. Specific Aim 2: To evaluate changes in folic acid levels and DNA methylation as a function of vitamin status during the development of resistance to cisplatin. Specific Aim 3: To evaluate the mechanisms by which high doses of folic acid alter resistance to cisplatin. These studies will tell us whether a vitamin used in cancer orthomolecular medical therapies and in cancer CAM is effective in preventing the development of resistance to commonly used cancer chemotherapeutic agents. We will compare very high folic acid concentrations, similar to what might be used in CAM treatment protocols, with deficient, normal and moderately elevated levels of folic acid, in order to get a clear picture of the effectiveness of very high doses of folic acid relative to the modest doses that would likely be tested in cancer patients in conventional clinical protocols.